Sustained limitation of myocardial reperfusion injury by a monoclonal antibody that alters leukocyte function

Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
Circulation (Impact Factor: 14.43). 02/1990; 81(1):226-37. DOI: 10.1161/01.CIR.81.1.226
Source: PubMed


Pentobarbital anesthetized dogs were subjected to 90 minutes of left circumflex coronary artery (LCCA) occlusion followed by 72 hours of reperfusion. Control or anti-Mo1 (904) F(ab')2 fragments of monoclonal antibodies were administered intravenously at a dose of 1 mg/kg beginning 45 minutes after occlusion and at a dose of 0.5 mg/kg at 12, 24, 36, and 48 hours after reperfusion. Myocardial infarct size expressed as a percentage of the area at risk (IN/AR) measured postmortem after 72 hours of reperfusion was significantly reduced by 904 F(ab')2 (21.6 +/- 2.8%, n = 8) compared with control F(ab')2 (37.4 +/- 5.8%, n = 8; p less than 0.025). There were no significant differences between groups in heart rate, mean arterial blood pressure, rate-pressure product, or LCCA blood flow that could account for a reduced infarct size. Regional myocardial blood flow (RMBF) was determined with 15-microns radiolabeled microspheres. Transmural blood flows (ml/min/g) within the region of myocardium at risk were not statistically different between treatment groups. Infarct size in both groups was related to regional myocardial blood flow, and the relation was shifted downward in the group treated with the anti-Mo1 F(ab')2 antibody (analysis of covariance, p = 0.01). Thus, anti-Mo1 F(ab')2 produces a sustained limitation of myocardial infarct size compared with controls under similar hemodynamic conditions and a similar degree of myocardial ischemia as determined by RMBF. These data suggest that inhibition of neutrophil adhesive interactions (as suggested by the inhibitory effect of anti-Mo1 on canine neutrophil aggregation) may be an effective mechanism for protection against myocardial injury secondary to myocardial ischemia and reperfusion.

Download full-text


Available from: Joseph C Fantone
  • Source
    • "Immunoblocking of the β2-integrin Mac-1 effectively alleviated ischemic reperfusion damage in the liver and heart by reducing neutrophil infiltration [51–53]. A monoclonal antibody targeting Mac-1 (CD11b) achieved similar effects with decreased intraparenchymal neutrophils after transient ischemia–reperfusion [54, 55]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Immunotherapy represents an active area of biomedical research to treat cancer, autoimmune diseases, and neurodegenerative disorders. In stroke, recanalization therapy is effective in reducing brain tissue damage after acute ischemic stroke. However, the narrow time window restricts its application for the majority of stroke patients. There is an urgent need to develop adjuvant therapies such as immunotherapy, stem cell replacement, and neuroprotective drugs. A number of molecules have been targeted for immunotherapy in stroke management, including myelin-associated proteins and their receptors, N-methyl-d-aspartic acid receptors, cytokines, and cell adhesion molecules. Both active vaccination and passive antibodies were tested in animal models of acute ischemic stroke. However, the mechanisms underlying the efficacy of immunotherapy are different for each target protein. Blocking myelin-associated proteins may enhance neuroplasticity, whereas blocking adhesion molecules may yield neuroprotection by suppressing the immune response after stroke. Although results from animal studies are encouraging, clinical trials using therapeutic antibodies failed to improve stroke outcome due to severe side effects. It remains a challenge to generate specific therapeutic antibodies with minimal side effects on other organs and systems.
    Full-text · Article · Oct 2013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background. We havepreviously demonstrated thatchemotactic factors released fromthe ischemic canine myocardium peakearly during reperfusion andthattheyelicit neutrophil adherence reactions invitro thataredependent on theCD18glycoprotein family. Inthisstudy we investigated thehypothesis thatneutrophil localization inischemic caninemyocardium in vivo occursovera similar timecourseduring early reperfusion andinvolves aCD18-dependent mechanism. Methods andResults. We occluded thecircumflex coronaryartery for1 hourinacute, open-chest dogs, followed byreperfusion for1,2,3,or4hours. Regional myocardial bloodflow was determined usingradiolabeled microspheres, andlocalization was traced usingtechne- tium-99m-labeled autologous neutrophils. Inthefirst hourofreperfusion, neutrophil localiza- tionoccurred preferentially within thesubendocardial regionandwas inversely related toflow. Neutrophil localization diminished acrosstheischemic myocardium fromendocardium to epicardium butremained negatively related toflowinthemidmyocardial region. Regardless of flow, little neutrophil localization occurred inthesubepicardial region. Neutrophil localization was greatest in thefirst hourofreperfusion anddiminished thereafter. By 4 hoursof reperfusion, therateoflocalization was markedly attenuated relative to1hour.Dogsgiven anti-CD18 monoclonal antibody R15.7(1mg/kgi.v.) before occlusion underwent 1hourof occlusion followed by1hourofreperfusion. Whencompared with1-hourreperfusion controls, theR15.7-treated dogsdemonstrated significant attenuation ofneutrophil localization inthe subendocardial region. Conclusions. Thesedatasupport theconcepts thatrapidneutrophil localization during reperfusion occurswithin regionsofprevious myocardial ischemia andthatneutrophils preferentially localize within thesubendocardial region. Therateofneutrophil localization is greatest within thefirst hourafter theinitiation ofreperfusion, andlocalization is, atleast in part,CD18dependent. Therapies directed against neutrophil-mediated reperfusion injury should beinitiated withthese considerations inmind.(Circulation 1991;84:400-411)
    Full-text · Article ·
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To determine if inhibition of leukocyte adhesion and aggregation could improve postischemic ventricular dysfunction ("stunning"), a monoclonal antibody (904) that binds to the adhesion-promoting Mo1 glycoprotein on the cell surface of leukocytes was administered intravenously (0.5 mg/kg) to open-chest dogs before a 15-minute coronary occlusion. Ultrasonic crystals placed in ischemic and control myocardium were used to measure systolic wall thickening during a 15-minute occlusion of the left anterior descending artery and for 3 hours after reperfusion. Myocardial blood flow was measured with tracer-labeled microspheres before occlusion, after 10 minutes of occlusion, 3 minutes of reperfusion, and at 1 and 3 hours after reperfusion. Six animals receiving anti-Mo1 antibody had antibody excess demonstrated with immunofluorescence techniques at 5 minutes and 3 hours of reperfusion; this finding indicated saturation of binding sites. Five animals served as controls and received an antibody (murine immunoglobulin G) that does not influence neutrophils. The two groups did not differ hemodynamically during ischemia and reperfusion. Risk areas and myocardial blood flow were also not significantly different between the two groups. The main parameter used to define regional myocardial stunning, percentage systolic wall thickening in the ischemic/reperfused area, did not differ significantly between the two groups. Specimens from nonischemic myocardium were compared with ischemic specimens for myeloperoxidase content. There were no significant differences within or between groups. These data indicate that the anti-Mo1 monoclonal antibody (904) is not effective in improving the profound myocardial dysfunction that persists for 3 hours of reperfusion after 15 minutes of ischemia.
    Full-text · Article · Nov 1989 · Circulation Research
Show more